BCG Vaccination to Protect Healthcare Workers Against COVID-19 (BRACE)

• ClinicalTrials.gov Identifier: NCT04327206
• Recruitment Status: Completed
• First Posted: March 31, 2020
• Last Update Posted: September 1, 2022
• Sponsor: Murdoch Childrens Research Institute
• Collaborators: Royal Children's Hospital; Bill and Melinda Gates Foundation
• Information provided by (Responsible Party): Murdoch Childrens Research Institute

Study Description

Brief Summary:

Phase III, two-group multicentre, randomised controlled trial in up to 10 078 healthcare workers to determine if BCG vaccination reduces the incidence and severity of COVID-19 during the 2020 pandemic.

Condition or disease	Intervention/treatment	Phase
Coronavirus Disease 2019 (COVID-19); Respiratory Illness; Corona Virus Infection; COVID-19	Drug: BCG Vaccine; Drug: 0.9%NaCl	Phase 3

Detailed Description:

Healthcare workers are at the frontline of the coronavirus disease (COVID-19) pandemic. They will be randomised to receive a single dose of BCG vaccine or 0.9% NaCl placebo. Participants will be followed-up for 12 months with notification from a Smartphone application or phone calls (up to daily when ill) and surveys to identify and detail COVID-19 infection. Additional information on severe disease will be obtained from hospital medical records and/or government databases. Blood samples will be collected prior to randomisation and at 3, 6, 9 and 12 months to determine exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Where required, swab/blood samples will be taken at illness episodes to assess SARS-CoV-2 infection.

The trial includes a pre-planned meta-analysis with data from 2834 participants recruited in the Stage 1 of this study, where participants were randomised to receive BCG or no BCG vaccine at the time of receiving influenza vaccination.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 6828 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Phase III, two group, multicentre, randomised controlled trial
• Masking: Double (Participant, Outcomes Assessor)
• Masking Description: The control group will receive a placebo of 0.9% sodium chloride (NaCl). Members of the research team doing the follow-up of participants and analysis will be blinded to the group allocation (by the removal of this variable and all other variables related to BCG from the dataset) until the formal detailed statistical analysis plan is confirmed and signed by all investigators and all data cleaning/preparation is complete.
• Primary Purpose: Prevention
• Official Title: BCG Vaccination to Reduce the Impact of COVID-19 in Healthcare Workers (BRACE) Trial
• Actual Study Start Date: March 30, 2020
• Actual Primary Completion Date: November 10, 2021
• Actual Study Completion Date: May 27, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: BCG vaccine; Participants will receive a single dose of BCG vaccine (BCG-Denmark). The adult dose of BCG vaccine is 0.1 mL injected intradermally over the distal insertion of the deltoid muscle onto the humerus (approximately one third down the upper arm).	Drug: BCG Vaccine; Freeze-dried powder: Live attenuated strain of Mycobacterium bovis (BCG), Danish strain 1331. Each 0.1 ml vaccine contains between 200000 to 800000 colony forming units. Adult dose is 0.1 ml given by intradermal injection; Other Names: Bacille Calmette-Guerin Vaccine; Bacillus Calmette-Guerin Vaccine; Statens Serum Institute BCG vaccine; Mycobacterium bovis BCG (Bacille Calmette Guérin), Danish Strain 1331; BCG Denmark
Placebo Comparator: 0.9% Saline; Participants will receive a single 0.1 mL dose of 0.9%NaCl injected intradermally over the distal insertion of the deltoid muscle onto the humerus (approximately one third down the upper arm).	Drug: 0.9%NaCl; 0.9% Sodium Chloride Injection; Other Name: 0.9% Saline

Outcome Measures

Primary Outcome Measures :

1. Symptomatic COVID-19 by 6 months [ Time Frame: Measured over the 6 months following randomisation ]

   Number of participants with Symptomatic COVID-19 defined as

   • positive SARS-Cov-2 test (PCR, RAT or serology), plus
   • fever (using self-reported questionnaire), or
   • at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure (using self-reported questionnaire)
2. Severe COVID-19 incidence over 6 months [ Time Frame: Measured over the 6 months following randomisation ]

   Number of participants with severe COVID-19 defined as:

   • positive SARS-CoV-2 test (PCR, RAT or serology), PLUS
   • death as a consequence of COVID-19, OR
   • Hospitalised as a consequence of COVID-19, OR
   • Non-hospitalised severe disease as a consequence of COVID-19, defined as non- ambulant* for ≥ 3 consecutive days unable to work** for ≥ 3 consecutive days

   (*) "pretty much confined to bed (meaning finding it very difficult to do any normal daily activities".

   (**) "I do not feel physically well enough to go to work"

Secondary Outcome Measures :

1. Symptomatic COVID-19 by 12 months [ Time Frame: Measured over the 12 months following randomisation ]

   Number of participants symptomatic COVID-19 disease defined as

   • positive SARS-Cov-2 test (PCR, RAT or serology), plus
   • fever (using self-reported questionnaire), or
   • at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure (using self-reported questionnaire)
2. Severe COVID-19 incidence over 12 months [ Time Frame: Measured over the 12 months following randomisation ]

   Number of participants with severe COVID-19 defined as:

   • positive SARS-CoV-2 test (PCR, RAT or serology), PLUS
   • death as a consequence of COVID-19, OR
   • Hospitalised as a consequence of COVID-19, OR
   • Non-hospitalised severe disease as a consequence of COVID-19, defined as non- ambulant* for ≥ 3 consecutive days unable to work** for ≥ 3 consecutive days

   (*) "pretty much confined to bed (meaning finding it very difficult to do any normal daily activities".

   (**) "I do not feel physically well enough to go to work"

3. Time to first symptom of COVID-19 [ Time Frame: Measured over the 6 and 12 months following randomisation ]

   Participants who had either a symptomatic or severe COVID-19 episode will have time to first symptom of COVID-19 calculated as:

   [Date of any symptom onset for the first symptomatic or severe COVID-19 episode - Date of randomisation]

   Participants who have not had a symptomatic or severe COVID-19 episode will have time calculated as:

   [Earliest censoring date - date of randomisation]

4. Number of Episodes of COVID-19 [ Time Frame: Measured over the 6 and 12 months following randomisation ]
   The total number of symptomatic or severe COVID-19 episodes (refer to outcome 3 and 4 for definitions)
5. Asymptomatic SARS-CoV-2 infection [ Time Frame: Measured over the 6 and 12 months following randomisation ]

   Number of participants with asymptomatic SARS-CoV-2 infection defined as

   • Evidence of SARS-CoV-2 infection (by seroconversion)
   • Absence of respiratory illness (defined by trigger or non-trigger symptoms)(using self- reported questionnaire)
   • No evidence of exposure prior to randomisation
6. Work absenteeism due to COVID-19 [ Time Frame: Measured within 6 and 12 months following randomisation ]

   Number of days (using self-reported questionnaire) unable to work (excludes quarantine/workplace restrictions) due to COVID-19 defined as

   • positive SARS-Cov-2 test (PCR, RAT or serology), plus
   • fever (using self-reported questionnaire), or
   • at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure (using self-reported questionnaire)
7. Bed confinement due to COVID-19 [ Time Frame: Measured over 6 and 12 months following randomisation ]

   Number of days confined to bed (using self-reported questionnaire) due to COVID-19 disease defined as

   • positive SARS-Cov-2 test (PCR, RAT or serology), plus
   • fever (using self-reported questionnaire), or
   • at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure (using self-reported questionnaire)
8. Symptom duration of COVID-19 [ Time Frame: Measured over 6 and12 months following randomisation ]

   Number of days with symptoms in any episode of illness that meets the case definition for COVID-19 disease:

   • positive SARS-Cov-2 test (PCR, RAT or serology), plus
   • fever (using self-reported questionnaire), or
   • at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure (using self-reported questionnaire)
9. Pneumonia due to COVID-19 [ Time Frame: Measured over the 6 and 12 months following randomisation ]
   Number of pneumonia cases (using self-reported questionnaire and/or medical/hospital records) due to COVID-19
10. Oxygen therapy due to COVID-19 [ Time Frame: Measured over the 6 and12 months following randomisation ]
    Need for oxygen therapy (using self-reported questionnaire and/or medical/hospital records) due to COVID-19
11. Critical care admissions due to COVID-19 [ Time Frame: Measured over the 6 and 12 months following randomisation ]
    Number of admission to critical care (using self-reported questionnaire and/or medical/hospital records) due to COVID-19
12. Mechanical ventilation due to COVID-19 [ Time Frame: Measured over the 12 months following randomisation ]
    Number of participants needing mechanical ventilation (using self-reported questionnaire and/or medical/hospital records)
13. Hospitalisation duration with COVID-19 [ Time Frame: Measured over the 6 and 12 months following randomisation ]
    Number of days of hospitalisation due to COVID-19 (using self-reported questionnaire and/or medical/hospital records).
14. Mortality due to COVID-19 [ Time Frame: Measured over the 6 and 12 months following randomisation ]
    Number of deaths due to COVID-19
15. Fever or respiratory illness [ Time Frame: Measured over the 12 months following randomisation ]

    Respiratory illness using self-reported questionnaire defined as:

    • at least one sign or symptom of respiratory disease including cough, sore throat, shortness of breath, respiratory distress/failure, or runny/blocked nose (in combination with another respiratory symptom or fever).
16. Severe fever or respiratory illness [ Time Frame: Measured over the 12 months following randomisation ]

    Severe fever or respiratory illness using self-reported questionnaire defined as:

    • Death, or
    • Hospitalised, or
    • Non-hospitalised severe disease, defined as non-ambulant1 for ≥ 3 consecutive days or unable to work2 for ≥ 3 consecutive days
17. Episodes of fever or respiratory illness [ Time Frame: Measured over the 12 months following randomisation ]

    Respiratory illness using self-reported questionnaire defined as:

    • at least one sign or symptom of respiratory disease including cough, sore throat, shortness of breath, respiratory distress/failure, or runny/blocked nose (in combination with another respiratory symptom or fever).
18. Work absenteeism due to fever or respiratory illness [ Time Frame: Measured over the 12 months following randomisation ]

    Number of days (using self-reported questionnaire) unable to work (excludes quarantine/workplace restrictions) due to fever or respiratory illness defined as

    • fever (using self-reported questionnaire), or
    • at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure, runny/blocked nose (using self-reported questionnaire)
19. Bed confinement due to fever or respiratory illness [ Time Frame: Measured over the 12 months following randomisation ]

    Number of days confined to bed (using self-reported questionnaire) due to fever or respiratory illness defined as

    • fever (using self-reported questionnaire), or
    • at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure, runny/blocked nose (using self-reported questionnaire)
20. Symptom duration of fever or respiratory illness [ Time Frame: Measured over the 12 months following randomisation ]

    Number of days with symptoms in any episode of illness that meets the case definition for fever or respiratory illness:

    • fever (using self-reported questionnaire), or
    • at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure, runny/blocked nose (using self-reported questionnaire)
21. Pneumonia within a febrile or respiratory illness [ Time Frame: Measured over the 12 months following randomisation ]
    Number of pneumonia cases(using self-reported questionnaire and/or medical/hospital records)
22. Oxygen therapy for a febrile or respiratory illness [ Time Frame: Measured over the 12 months following randomisation ]
    Need for oxygen therapy (using self-reported questionnaire and/or medical/hospital records)
23. Critical care admissions for a febrile or respiratory illness [ Time Frame: Measured over the 12 months following randomisation ]
    Number of admission to critical care (using self-reported questionnaire and/or medical/hospital records)
24. Mechanical ventilation for a febrile or respiratory illness [ Time Frame: Measured over the 12 months following randomisation ]
    Number of participants needing mechanical ventilation (using self-reported questionnaire and/or medical/hospital records)
25. Mortality as a consequence of an episode of fever or respiratory illness [ Time Frame: Measured over the 12 months following randomisation ]
    Number of deaths
26. Hospitalisation duration for a febrile or respiratory illness [ Time Frame: Measured within 6 and 12 months following randomisation ]
    Number of days of hospitalisation due to fever or respiratory illness (using self-reported questionnaire, medical/hospital records)
27. Unplanned work absenteeism for an acute illness or hospitalisation [ Time Frame: Measured over the 6 and 12 months following randomisation ]
    Number of days of unplanned absenteeism for any reason (using self-reported questionnaire)
28. Local and systemic adverse events to BCG vaccination in healthcare workers [ Time Frame: Measured over the 3 months following randomisation ]
    Adverse events (AEs), over the 3 months following randomisation, by type, severity (graded using toxicity grading scale), relationship to intervention of adverse events (AEs) of interest.
29. Serious Adverse Events (SAEs) to BCG vaccination in healthcare workers [ Time Frame: Measured over the 3 months following randomisation ]
    SAEs over the 3 months following randomisation, by type, severity (graded using toxicity grading scale), relationship to intervention.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Over 18 years of age

• Healthcare worker

  • This is defined as anyone who works in a healthcare setting or has face to face contact with patients.
• Provide a signed and dated informed consent form
• Australian sites only: If annual influenza vaccination is available, receiving the flu vaccine is an eligibility requirement. The flu vaccine will be required a minimum of 3 days in advance of randomisation in the BRACE trial.
• Pre-randomisation blood collected

Exclusion Criteria:

• Has any BCG vaccine contraindication

  • Fever or generalised skin infection (where feasible, randomisation can be delayed until cleared)
  • Weakened resistance toward infections due to a disease in/of the immune system

  • Receiving medical treatment that affects the immune response or other immunosuppressive therapy in the last year.

    • These therapies include systemic corticosteroids (≥20 mg for ≥2 weeks), non-biological immunosuppressant (also known as 'DMARDS'), biological agents (such as monoclonal antibodies against tumour necrosis factor (TNF)-alpha).
  • People with congenital cellular immunodeficiencies, including specific deficiencies of the interferon-gamma pathway
  • People with malignancies involving bone marrow or lymphoid systems

  • People with any serious underlying illness (such as malignancy)

    • NB: People with cardiovascular disease, hypertension, diabetes, and/or chronic respiratory disease are eligible if not immunocompromised, and if they meet other eligibility criteria
  • Known or suspected HIV infection,even if they are asymptomatic or have normal immune function.
  • This is because of the risk of disseminated BCG infection
  • People with active skin disease such as eczema, dermatitis or psoriasis at or near the site of vaccination
  • A different adjacent site on the upper arm can be chosen if necessary

  • Pregnant

    • Although there is no evidence that BCG vaccination is harmful during pregnancy, it is a contra-indication to BCG vaccination. Therefore, we will exclude women who think they could be pregnant or are planning to become pregnant within the next month.
    • UK specific: Although there is no evidence that BCG vaccination is harmful during pregnancy, it is a contra-indication to BCG vaccination. Therefore, we will exclude women of childbearing potential (WOCBP) who think they could be pregnant.
    • Spain specific: If the patient is female, and of childbearing potential, she must have a negative pregnancy test at the time of inclusion and practice a reliable method of birth control for 30 days after receiving the BCG vaccination.
  • Another live vaccine administered in the month prior to randomisation

  • Require another live vaccine to be administered within the month following BCG randomisation

    • If the other live vaccine can be given on the same day, this exclusion criteria does not apply
  • Known anaphylactic reaction to any of the ingredients present in the BCG vaccine
  • Previous active TB disease
  • Currently receiving long term (more than 1 month) treatment with isoniazid, rifampicin or quinolone as these antibiotics have activity against Mycobacterium bovis
• Previous adverse reaction to BCG vaccine (significant local reaction (abscess) or suppurative lymphadenitis)
• BCG vaccine given within the last year
• Have previously had a SARS-CoV-2 positive test result (positive PCR on a respiratory sample or a positive SARS-CoV-2 diagnostic antigen test approved by the local jurisdiction's public health policy)
• Already part of this trial, recruited at a different site/hospital.
• Participation in another COVID-19 prevention trial
• Have previously received a COVID-19-specific vaccine

Contacts and Locations

Locations

Australia, New South Wales

St Vincent's Hospital, Sydney

Sydney, New South Wales, Australia, 2010

Prince of Wales Hospital

Sydney, New South Wales, Australia, 2031

Sydney Children's Hospital, Randwick

Sydney, New South Wales, Australia, 2145

The Children's Hospital at Westmead

Sydney, New South Wales, Australia, 2145

Westmead Hospital

Sydney, New South Wales, Australia, 2145

Australia, South Australia

Royal Adelaide Hospital

Adelaide, South Australia, Australia, 5000

Women's and Children's Hospital

North Adelaide, South Australia, Australia, 5006

Australia, Victoria

Royal Children's Hospital

Melbourne, Victoria, Australia, 3052

Epworth Richmond

Melbourne, Victoria, Australia, 3121

Monash Health- Monash Medical Centre

Melbourne, Victoria, Australia, 3168

Australia, Western Australia

Fiona Stanley Hospital

Murdoch, Western Australia, Australia, 6150

Perth Children's Hospital

Perth, Western Australia, Australia, 6009

Sir Charles Gairdner Hospital

Perth, Western Australia, Australia, 6009

Brazil

Fundação de Medicina Tropical Dr Heitor Vieira Dourado (FMT-HVD)

Manaus, Amazonas, Brazil, 69040-000

Santa Casa Hospital

Campo Grande, Mato Grosso Do Sul, Brazil, 79002-230

CASSEMS Hospital

Campo Grande, Mato Grosso Do Sul, Brazil, 79002-251

Federal University of Mato Grosso do Sul

Campo Grande, Mato Grosso Do Sul, Brazil, 79070-900

Hospital Regional de Mato Grosso do Sul

Campo Grande, Mato Grosso Do Sul, Brazil, 79084-180

Centro de Estudos da Saúde do Trabalhador e Ecologia Humana

Rio de Janeiro, RJ, Brazil, 22780-195

Centro de Referência Prof Hélio Fraga

Rio de Janeiro, RJ, Brazil, 22780-195

Netherlands

Noord West Ziekenhuis

Alkmaar, Netherlands, 1815 JD

Rijnstate Hospital

Arnhem, Netherlands, 6815 AD

Amphia Hospital

Breda, Netherlands, 4818 CK

St Antonius Hospital

Nieuwegein, Netherlands, 3435 CM

Radboud UMC

Nijmegen, Netherlands, 6525 GA

University hospital in Utrecht (UMCU)

Utrecht, Netherlands, 3584 CX

Spain

University Hospital German Trias I Pujol

Badalona, Barcelona, Spain, 08916

Mutua Terrassa Univeristy Hospital

Terrassa, Barcelona, Spain, 08221

University Hospital Cruces

Barakaldo, Bizkaia, Spain, 48903

Marqués de Valdecilla University Hospital

Santander, Spain, 39008

University Hospital Virgen Macarena

Sevilla, Spain, 41009

United Kingdom

Teign Estuary Medical Group

Teignmouth, Devon, United Kingdom, TQ14 8AB

Ide Lane Surgery

Alphington, Exeter, United Kingdom, EX2 8UP

St Leonard's Practice

St Leonards, Exeter, United Kingdom, EX1 1SB

Travel Clinic

Exeter, United Kingdom, EX1 1PR

Royal Devon and Exeter NHS Foundation Trust

Exeter, United Kingdom, EX2 5DW

Sponsors and Collaborators

Murdoch Childrens Research Institute

Royal Children's Hospital

Bill and Melinda Gates Foundation

Investigators

• Principal Investigator: Prof Nigel Curtis; Murdoch Children's Research Institute

  Study Documents (Full-Text)

Documents provided by Murdoch Childrens Research Institute:

Study Protocol  [PDF] May 17, 2022

Statistical Analysis Plan  [PDF] August 10, 2022

Informed Consent Form  [PDF] September 14, 2020

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Pittet LF, Messina NL, Gardiner K, Orsini F, Abruzzo V, Bannister S, Bonten M, Campbell JL, Croda J, Dalcolmo M, Elia S, Germano S, Goodall C, Gwee A, Jamieson T, Jardim B, Kollmann TR, Guimaraes Lacerda MV, Lee KJ, Legge D, Lucas M, Lynn DJ, McDonald E, Manning L, Munns CF, Perrett KP, Prat Aymerich C, Richmond P, Shann F, Sudbury E, Villanueva P, Wood NJ, Lieschke K, Subbarao K, Davidson A, Curtis N; BRACE trial Consortium Group. BCG vaccination to reduce the impact of COVID-19 in healthcare workers: Protocol for a randomised controlled trial (BRACE trial). BMJ Open. 2021 Oct 28;11(10):e052101. doi: 10.1136/bmjopen-2021-052101.

Crisan-Dabija R, Grigorescu C, Pavel CA, Artene B, Popa IV, Cernomaz A, Burlacu A. Tuberculosis and COVID-19: Lessons from the Past Viral Outbreaks and Possible Future Outcomes. Can Respir J. 2020 Sep 5;2020:1401053. doi: 10.1155/2020/1401053. eCollection 2020.

• Responsible Party: Murdoch Childrens Research Institute
• ClinicalTrials.gov Identifier: NCT04327206
• Other Study ID Numbers: 62586; U1111-1256-4104 ( Registry Identifier: The Universal Trial Number (UTN) ); INV-017302 ( Other Grant/Funding Number: BILL & MELINDA GATES foundation )
• First Posted: March 31, 2020
• Last Update Posted: September 1, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

Under the terms of the funding agreement with the Bill and Melinda Gates foundation, the BRACE trial has a data sharing agreement in place.

An anonymised Individual Participant Data (IPD) dataset and a data dictionary will be provided to Vivli (https://vivli.org/) under the terms of the agreements with the Bill and Melinda Gates foundation grant and Vivli.

After database lock, the following may be made available long-term for use by future researchers from a recognised research institution whose proposed use of the data has been ethically reviewed and approved by an independent committee and who accept MCRI's conditions, under a collaborator agreement, for accessing:

• Individual participant data that underlie the results reported in our articles after deidentification (text, tables, figures and appendices)
• Study protocol, Statistical Analysis Plan, PICF

• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: After database lock, a 12-month embargo period will be in place, to allow adequate time for analyses and publication outputs. Data transfer to Vivli should occur during the embargo period.

Access Criteria

Researchers from a recognised research institution can approach MCRI for access of data.

The researcher will need to provide evidence that the proposed use of the data has been ethically reviewed and approved by an Institutional Review Board (IRB)/ Human Research Ethics Committee(HREC), and accept MCRI's conditions, under a collaborator agreement.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

COVID-19; Coronavirus Infections; Respiratory Tract Infections; Infections; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Vaccines; BCG Vaccine; Immunologic Factors; Physiological Effects of Drugs; Adjuvants, Immunologic